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.com
Volume 7, Issue 4 (Suppl)
J Biotechnol Biomater, an open access journal
ISSN: 2155-952X
Bio America 2017
October 19-20, 2017
October 19-20, 2017 | New York, USA
18
th
Biotechnology Congress
AHCY inhibitors cause growth inhibition of prostate cancer via induction of mir-26a
Noriko Uchiyama
1
and
Tomohiro Kawamoto
2
1
Takeda Pharmaceuticals International Co., Boston, USA
2
Takeda Pharmaceutical Company Limited, Kanagawa, Japan
M
ost prostate cancers initially respond to androgen deprivation therapy, but then progress fromandrogen-dependent to androgen-
independent prostate cancers. In the present study, a differential cytotoxicity screen of hormone-resistant prostate cancer
LNCaP-hr cells and the parental LNCaP-FGC cells against normal MRC5 fibroblast cells, identified a small molecule compound,
Aristeromycin (a derivative of 3-deazaneplanocin A (DZNeP)). The molecular target was shown to be S-adenosylhomocysteine
hydrolase (AHCY), which catalyzes reversible hydrolysis of S-adenosylhomocysteine (SAH) to adenosine and L-homocysteine.
DZNeP and Aristeromycin showed high inhibitory activity against AHCY. Treatment of the prostate cancer cells with DZNeP led
to SAH accumulation and decreased levels of homocysteine and histone H3K27 methylation. SAH accumulation and cell growth
inhibition were confirmed after siRNA-mediated AHCY knockdown. To further understand why AHCY inhibitors decreased
prostate cancer cell growth, we performed microRNA expression profiling with LNCaP-hr cells. Mir-26a, which is involved in
regulation of EZH2 expression, was upregulated in Aristeromycin-treated LNCaP-hr cells. A reporter assay established with the
EZH2 3α-UTR confirmed that transfection of microRNA precursor molecules for miR-26a decreased the EZH2 3α-UTR luciferase
activity. Meanwhile, an antisense microRNA inhibitor for miR-26a recovered the luciferase activity. The present findings suggest, at
least in part, that miR-26a induced by an AHCY inhibitor can regulate oncogenic EZH2 expression, and could thus be an important
mechanism of action for AHCY inhibitors in the treatment of prostate cancer.
Biography
Noriko Uchiyama is a Researcher of Investigative Toxicology of Drug Safety Research Evaluation, Takeda Pharmaceuticals International Co. Her work is devoted to the
cutting-edge biotechnologies to identify, understand and de-risk toxicities in Takeda’s next generation of medicines. The team develops and validates predictive
in-vitro
models of toxicology for use in early compound screening to estimate risk of a specific toxicity. Other topics of her work are the drug discovery process e.g. establishment of
in-vitro
assay system of enzyme and cell-based assay, screening and evaluation of compounds, narrowing good chemotypes in the drug discovery projects. Her expertise is
cell pharmacology in the Oncology therapeutic target including kinase, protease, nuclear-receptor, channel etc. She is involved in drug discovery for novel drugs from both
perspectives i.e.
in-vitro
mechanistic investigation of efficacy of targets and downstream pathways leading to toxicity to drive project to safer chemistry.
noriko.uchiyama@takeda.comNoriko Uchiyama et al., J Biotechnol Biomater 2017, 7:4 (Suppl)
DOI: 10.4172/2155-952X-C1-079